Note that detection of minimal residual disease (MRD) by either PCR amplification techniques or flow cytometry is currently perhaps the strongest predictor of event-free survival (EFS) and overall survival (OS).

Predictive accuracy of risk stratification in pediatric acute lymphoblastic leukemia (ALL) was significantly reduced when a single threshold that didn't take genetic subtypes into account was used to assign patients to a minimal residual disease (MRD) risk group, according to researchers.

Analysis of early treatment response in a population-based cohort of patients treated in the Medical Research Council UKALL2003 trial and followed for a median of 7 years demonstrated that the relapse risk was correlated with MRD kinetics of distinct genetic subtypes, according to Anthony V. Moorman, MD, of Newcastle University, Newcastle upon Tyne, the UK, and colleagues.

"Integration of genetic subtype-specific MRD values allowed more refined risk group stratification," the study authors said. "Future risk algorithms should integrate genetics with MRD to accurately identify patients with the lowest and highest risk of relapse."

For a patient with an MRD value of 0.01% to < 0.1%, relapse risk was 12% for good-risk genetics, 18% for intermediate-risk genetics, and 40% for high-risk genetics, the study showed.

Similar differences were observed in rates of event-free survival (EFS) and overall survival (OS). Patients with good-risk genetics with MRD values of 0.01% to <0.1% had 5-year EFS and OS rates of 92% and 96%. Patients in the poor-risk genetic group with the same MRD response had rates of 73% and 73%, respectively.

"Although the risk of relapse was directly proportional to the MRD level within each genetic risk group, absolute relapse rate that was associated with a specific MRD value or category varied significantly by genetic subtype," the investigators pointed out.

Integrating MRD and genetic risk at diagnosis also made it possible to identify a small group of patients at high risk for relapse as candidates for second-line salvage therapy. This group included only 8% of patients but they experienced 48% of high-risk relapses in spite of good genetics and/or good MRD response to initial therapy.

Currently, treatment protocols don't take the presence of genetic abnormalities into account, using a a single MRD threshold to assign patients to risk groups, Moorman and colleagues noted.

Data from this study "indicate that MRD must be interpreted within the context of genetics to maximize its effectiveness," they emphasized, adding that using different MRD cutoffs for various genetic subtypes would allow for more flexible definitions of patient subgroups.

Once validated, subtype-specific MRD thresholds "will improve risk algorithms that are used to allocate treatment," they predicted.

In the analysis, MRD was measured at the end of induction for 2,678 patients defined by clinical features and sentinel genetic lesions using MRD as a continuous value.

High-risk (HR) relapses were composed of all early relapses (<18 months after diagnosis), all T-cell acute lymphoblastic leukemia (T-ALL) bone marrow (BM) relapses and, in patients with B-cell precursor ALL, early isolated marrow relapses. All other relapses were classified as standard risk.

"Examining MRD as a continuous variable emphasizes that the relationship between MRD level and outcome is a continuum and that using a single cutoff value to stratify patients is an oversimplification," the study authors wrote. "Moreover, integrating genetics aids the interpretation of this relationship and indicates that MRD alone is not sufficient to accurately stratify patients."

Patients with MRD values at either the high- or the low-end of the scale are the exceptions, they noted. For instance, patients with MRD ≥5% had an extremely poor outcome, with an EFS of 42% at 5 years regardless of genetics. These patients should be considered for treatment intensification or novel therapies, the researchers said.

At the other end of the scale, patients with a negative MRD response rate had an excellent outcome with an EFS rate of 95% at 5 years, and are potential candidates for treatment reduction to lower risk of toxicity.

Notably, when patients with undetectable MRD experience relapse, their disease is usually salvageable, the researchers said. There may also be a subset of patients "whose disease can be eradicated by weeks, rather than years, of therapy," they added, noting that this hypothesis will need to be tested using ultrasensitive MRD methodologies.

Bone marrow MRD response was not predictive of the risk of isolated CNS relapse, a finding in keeping with previous studies.

In an accompanying editorial, Stephen P. Hunger, MD, of Children's Hospital of Philadelphia, said the insights provided by this study make a case for more sophisticated use of MRD that moves beyond a single threshold for all patients.

"Overall, this is an important study that provides new insights into the complex interplay between clinical risk factors, tumor genomics, and MRD that is linked to relapse risk and outcome," Hunger wrote. "To develop true precision medicine strategies for pediatric patients with ALL, we must accept this challenge and use integrated models in clinical trial design."

Questions that remain include how to identify patients with a high chance of cure after initial therapy, and how to improve EFS and OS for those at high risk of relapse, he said.

Looking ahead, it will be interesting to see what impact advances in MRD technology have on these integrated-risk groups, Hunger pointed out, noting that high-throughput sequencing of immunoglobulin heavy-chain genes (IGH) is already making it possible to detect leukemia cells down to levels of 0.0001%.

"Optimistically, this might allow identification of an ultra-low-risk group with an relapse risk of 1% to 2% that accounts for only a small percentage of total relapses," Hunger said.

Accessibility Statement

At MedPage Today, we are committed to ensuring that individuals with disabilities can access all of the content offered by MedPage Today through our website and other properties. If you are having trouble accessing www.medpagetoday.com, MedPageToday's mobile apps, please email legal@ziffdavis.com for assistance. Please put "ADA Inquiry" in the subject line of your email.